IJCA-18122; No of Pages 6 International Journal of Cardiology xxx (2014) xxx–xxx
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Systematic review and meta-analysis of incidence and correlates of recurrence of takotsubo cardiomyopathy☆ Kuljit Singh a,⁎, Kristin Carson b, Zafar Usmani b, Gagandeep Sawhney c, Ranjit Shah a, John Horowitz a a b c
Dept. of Cardiology, Queen Elizabeth Hospital, University of Adelaide, Adelaide, SA 5000, Australia Dept. of Respiratory Medicine, Basil Hetzel Institute, University of Adelaide, Adelaide, SA 5000, Australia The Madison Practice, Suite 6, 25 Hunter St., Hornsby, NSW 2077, Australia
a r t i c l e
i n f o
Article history: Received 17 March 2014 Received in revised form 17 April 2014 Accepted 19 April 2014 Available online xxxx Keywords: Recurrence Takotsubo cardiomyopathy Stress cardiomyopathy
a b s t r a c t Aim: Takotsubo cardiomyopathy (TTC) is a disorder of myocardial inflammation induced by high catecholamine levels and is associated with acute complications. In the long-term TTC is associated with a risk of single or multiple recurrences, but risk of such occurrences is not clear. We performed a systematic review and meta-analysis to identify and consolidate the evidence on the incidence and clinical correlates of cases of TTC recurrence. Methods: A comprehensive search of four major databases (EMBASE, OVID Medline, PubMed and Google Scholar) was performed from their inception to first week of Jan 2014. We included original research studies, recruiting ≥5 participants, with ≥3 months follow-up, published in English language that reported data on recurrence in patients with TTC. Results: Out of 298 studies searched, 31 cohorts (1664 TTC patients) were included in the analyses. Out of 74 cases of recurrence, with a mean follow-up of 24.5 months (95% CI, 19.3 to 33 months), extensive recurrence data were available for 23 cases. Cumulative incidence of recurrence was approximately 5% at 6 years. Annual rate of recurrence was approximately 1.5%. Furthermore, 14% of cases had recurrent chest pain and 11% reported dyspnea without definite evidence of recurrent TTC. Discharge medications at index admission included β-adrenoceptor antagonists (BB) in 66.8% and ACE inhibitors (ACEi) and ARB in 67.4%. Recurrence rate was independent of clinic utilization of BB prescription, but inversely correlated (r = −0.45, p = 0.016) with ACEi/ARB prescription. Patients with severe TTC at index admission were noted to have more recurrences. Conclusions: (1) TTC is associated with only 1–2% annual recurrence rate but substantially greater frequency of ongoing symptoms. (2) ACEi/ARB rather than BB may reduce risk of recurrence. © 2014 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Takotsubo cardiomyopathy (TTC) is now a well-known cardiac condition that predominantly affects women and can be associated with acute and chronic complications. Interestingly, TTC was first reported only 25 years ago in Japan and one of the earliest descriptions in humans was even more recent [1]. The acute stage of the disease can be complicated by hypotension, shock, arrhythmias, heart failure and death [2]. While our understanding of acute complication is clear, the knowledge of the natural history and long term TTC complications is limited because of relatively small number and limited follow-up of the patients. Recurrence of TTC is common and is a well reported long
☆ Disclosures: None. ⁎ Corresponding author at: Dept. of Cardiology, Queen Elizabeth Hospital, University of Adelaide, SA 5000. Tel.: +61 433 698 945; fax: +61 8312 4919. E-mail address: [email protected] (K. Singh).
term issue in TTC cohort [3]. However, the exact incidence and correlates of recurrence are not known. We therefore performed a meta-analysis and systematic review to determine the global incidence of recurrence of TTC and to consolidate the evidence. In the current study, we sought to determine utilizing a systematic review/meta-analysis approach the incidence of recurrence of TTC episodes and cause of its variability. We also prospectively evaluated the impact of discharge medications, left ventricular ejection fraction (LVEF) and type of stressor during initial episode on recurrence. 2. Methods This systematic review and meta-analysis is reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement guidelines. We included comparative studies of any design (randomized control trials, cohort, case control and cross sectional). Eligible studies needed to have ≥5 patients and a minimum follow-up of 3 months with confirmed documentation of recurrence of TTC. Inclusion of studies was limited to English language and foreign studies where translation in English was available. When data was reported from interrelating study samples (e.g., publications from the same group), the study with the highest number of
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Please cite this article as: Singh K, et al, Systematic review and meta-analysis of incidence and correlates of recurrence of takotsubo cardiomyopathy, Int J Cardiol (2014), http://dx.doi.org/10.1016/j.ijcard.2014.04.221
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K. Singh et al. / International Journal of Cardiology xxx (2014) xxx–xxx
Search Database: PubMed, Ovid Medline, Embase, Google Scholar Search Date: January 31, 2014. Search Strategy: (Takotsubo Cardiomyopath* or Broken Heart Syndrome or Stress Cardiomyopathy or Apical Ballooning Syndrome or Takotsubo Cardiomyopath*) and (Recurrence [MH] OR Recurrenc*[TW] OR Relapse*[TW] OR Reappearance*[TW] OR Incidence*[TW] OR Prevalence*[TW] OR Recurrent*[TW])
298 Abstracts were screened by for inclusion/exclusion criteria
6 Duplicate studies 12 follow up less than 3 months 3 Systematic reviews 4 studies did not report events during follow up 3 articles in foreign language without any translation in English 2 articles with less than 5 patients during follow up
240 abstracts were excluded based on screening of abstracts and titles for general criteria for inclusion and exclusion.
58 articles were selected for full-text review
28 articles were selected from the search + 3 other articles were selected from citations of other articles on TTC
31 articles fulfilled inclusion criteria and were selected for systematic review 1. ≥ 5 patients 2. ≥ 3 months of follow up provided 3. Incidences of recurrence during follow up clearly mentioned.
Fig. 1. Schematic of database search and identification of studies.
patients and the longest follow-up was included in the analysis. Single case reports, case series with less than 5 patients or where the follow-up was not conducted were not included. Systematic reviews of TTC were not included in the analysis. A thorough computer based search was performed using OVID MEDLINE, EMBASE, Google Scholar and PubMed databases. Search terms included (Takotsubo Cardiomyopath* [TW] OR Broken Heart Syndrome [TW] OR Stress Cardiomyopathy [TW] OR Apical Ballooning Syndrome [TW] OR Tako-Tsubo Cardiomyopath* [TW])) and (Recurrence [MH] OR Recurrence*[TW] OR Relapse*[TW] OR Reappearance*[TW] OR Incidence*[TW] OR Prevalence*[TW] OR Recurrent*[TW]). No limit to the start date was applied and the search was conducted up to 31 January 2014. We hand searched the references cited in the previous reviews and important articles on recurrence on TTC. We contacted the corresponding authors of the studies where relevant information was missing [4]. Two reviewers (KS and RS) screened all titles and abstracts individually. This was followed by the full manuscript review of the selected articles by the reviewers. One reviewer (KS) extracted data independently from selected studies using a standardized, pilot tested extraction template. The following data was extracted: study characteristics (author, country where investigation was conducted, study design, number of participants and objective of the study), participant characteristics (age and gender), clinical characteristics (ACS type for TTC, predisposing physical and emotion stressors, left ventricular ejection fraction (LVEF), acute complications, acute mortality, length of stay, discharge medications), recurrences (number and time of recurrence after initial diagnosis) and complications during long term follow up (death, chest pain, dyspnea, fatigue and heart failure). Two reviewers (RS and KS) assessed quality of included studies using a sub-set of the Tooth et.al, manuscript titled ‘Quality of Reporting of Observational Longitudinal Research’ [5], including only the 23 quality domains relevant to a meta-analysis of observational studies. We evaluated potential biases using classifications of ‘low risk of bias’ when data for the criterion were described, ‘high risk of bias’ when data were not stated and ‘unclear risk of bias’ when the criterion was not relevant to the study design. Review Manager software version 5.2 was used to make the risk of bias graph. Any classification, which was not straightforward, was solved by discussion with a third reviewer KC.
Continuous variables were reported as means ± standard deviation (SD), while skewed data were described as medians ± interquartile range. Categorical variables were reported using odds ratios (OR) with 95% confidence intervals (CI). If formal metaanalysis was not possible due to a skewed distribution of the number of patients between each study, we overlooked the individual studies and used data as if obtained from a single study. Studies with missing data were excluded from meta-analyses and details extrapolated in the quality and risk of bias assessments. We then used logistic regression to assess the relationship. Significant interaction between variables was considered when P b 0.05. All calculations were performed using Review Manager (RevMan, Computer program, Version 5.2, Copenhagen, The Nordic Cochrane Centre, The Cochrane Collaboration, 2012), SPSS 18.0 software (SPSS, IL, USA) and Microsoft Excel 2010. We divided the studies above and below the median level of percentage of ACE/ARB, BB and recurrence rate and performed Chi square test. The annual incidence of recurrence per hundred patients for each individual study was calculated. Formula for a CI for a population proportion was used to obtain CI for annual recurrence for each individual study.
3. Results The literature search on TTC and recurrence yielded 298 citations. The abstracts of all the 298 citations were reviewed and 58 articles were chosen for full text review. Of the 58 articles chosen for the full text review, 34 were selected as per the inclusion and exclusion criteria. Six out of 34 studies were noted to be duplicated (from the same group with overlapping patient data sets) and were excluded. Additional 3 articles were found on the hand search leading to a total of 31 [23,24, 25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47, 48,49,50,51,52,53] articles in the systematic review (Fig. 1). Authors
Please cite this article as: Singh K, et al, Systematic review and meta-analysis of incidence and correlates of recurrence of takotsubo cardiomyopathy, Int J Cardiol (2014), http://dx.doi.org/10.1016/j.ijcard.2014.04.221
K. Singh et al. / International Journal of Cardiology xxx (2014) xxx–xxx
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Table 1 Summary of basic characteristics of 32 studies included in this systematic review. No.
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31
Author
Year published
11
Kurowski V Traulle S12 Previtali M13 Eshtehardi P14 Spedicato L15 Mhmoud RE16 Regnate RE17 Dib C18 Teh AW19 Sharkey SW20 Primetshofer D21 Song BG22 Opolski G23 Lee PH24 Parodi G25 Samardhi H26 Maekawa Y27 Pawlak M28 Brenner R29 Núñez-Gil IJ30 Cacciotti L31 Vriz O32 Patel SM33 Sharma V34 Showkathali R35 Pullara36 Ribeiro VF37 Abdulla I38 Tsuchihashi K39 Hertting K40 Desmet WJR41
2007 2008 2009 2009 2008 2009 2009 2009 2010 2010 2010 2010 2010 2010 2011 2011 2011 2012 2012 2012 2012 2013 2013 2012 2013 2013 2013 2006 2001 2006 2003
Country
Germany France Italy Switzerland Italy France USA USA Australia USA Austria South Korea Poland South Korea Italy Australia USA/Japan Poland Switzerland Spain Italy Italy USA UK UK Italy Portugal Australia Japan Germany Belgium
TTC cases
35 14 18 41 29 32 70 105 23 136 31 87 31 56 116 52 46 41 17 100 75 25 224 12 17 26 37 35 88 32 13
Mean age (yrs)
72 70.4 72 65 64 71 67 66 65 68 75 NA 67 64 73 64 NA 69 66 68 72 66.8 NA 68 70 71 63 68 67 67.5 62.5
Gender
Mode of presentation
Variant
Presenting symptom
Women
Men
STEMI
NSTEMI
Apical
Non-apical
Chest pain
Dyspnoea
Other
33 13 18 35 25 31 67 100 20 130 28 64 29 44 106 51 43 39 17 89 72 21 212 10 17 22 35 35 76 29 12
2 1 0 6 4 1 3 5 3 6 3 23 2 20 10 1 3 2 0 11 3 4 12 2 0 4 2 1 12 3 1
24 7 10 16 18 17 29 35 16 67 13 28 24 16 70 10 29 29 5 60 34 20 101 4 17 NA 15 NA 79 12 4
11 7 8 25 11 15 41 70 7 69 8 59 7 40 46 42 14 12 12 40 41 5 123 8 0 NA 22 NA 9 20 9
21 NA NA 33 NA 28 NA NA NA 72 NA 55 NA 48 106 41 NA NA 16 NA 69 NA NA 12 NA 26 34 21 NA NA NA
14 NA NA 8 NA 4 NA NA NA 64 NA 32 NA 8 10 11 NA NA 1 NA 6 NA NA 0 NA 0 3 14 NA NA NA
NA 11 17 31 25 30 54 81 23 85 24 43 29 10 85 48 31 38 12 88 48 18 NA NA NA 26 33 NA 59 18 8
NA 4 2 10 3 1 28 8 NA 25 10 34 12 26 Na 6 24 14 5 NA 11 5 NA NA NA NA 3 NA 6 7 5
NA 0 1 NA 2 2 6 16 NA 26 1 0 20 NA 3 NA NA NA NA NA 4 NA NA NA NA 1 NA 23 7 NA
TTC = takotsubo cardiomyopathy. STEMI = ST elevation myocardial infarction. NSTEMI = non ST elevation myocardial infarction. UK = United Kingdom. USA = United States of America. NA = not available.
were contacted to obtain details of the patients with recurrence where it was not reported in the study. All the study designs were observational, including 20 retrospective, 10 prospective and one partially retrospective and partially prospective. Sample size ranged from 12 to 224 participants (total 1664). Twenty of these studies were from Europe, 3 were from Asia, 4 from the United States of America (USA), 3 from Australia and 1 study included participants from both USA and Japan. Basic characteristics of the studies are detailed in Table 1. Among the whole cohort of 1664 patients with TTC, 91.5% (n = 1523) were
women. The mean age of patients was 66 years (95% CI 63 to 69 years). In nearly 74% of patients TTC was preceded by physical/emotional stress and in the remaining 26% no obvious stressor was identified. Approximately 52% of patients presented as ST elevation myocardial infarction (STEMI) and the rest as non ST elevation myocardial infarction (NSTEMI). Presenting symptoms included chest pain in nearly 73% of cases and dyspnea in 18%, while in nearly 8% of patients TTC was diagnosed incidentally without either chest pain or dyspnea. Moderate LV systolic dysfunction was present in most of the patients with mean LVEF of 40% (95% CI 39% to 41%).
Fig. 2. Adjusted rate of recurrence per 100 patients per year among the studies included in the systematic review (shown in percentage).
Please cite this article as: Singh K, et al, Systematic review and meta-analysis of incidence and correlates of recurrence of takotsubo cardiomyopathy, Int J Cardiol (2014), http://dx.doi.org/10.1016/j.ijcard.2014.04.221
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K. Singh et al. / International Journal of Cardiology xxx (2014) xxx–xxx
Fig. 3. Accumulative incidence of recurrence of takotsubo cardiomyopathy at 6-month intervals.
Acute complications were common. Death during index admission occurred in 3.5% of TTC cases. Acute heart failure was noted in 28% of cases, acute pulmonary odema in 21% and shock in 8% of the patients. Intubation, insertion of intra-aortic balloon pump and inotropic support during the shock/heart failure was common and the frequency of use varied from 7% to 18% in the studies mentioning this complication. Average length of hospital stay was 6.4 days (95% CI, 4.8 to 8 days). Nearly 80% of patients were discharged on anti-platelet medications (aspirin or clopidogrel). Angiotensin converting enzyme inhibitor/angiotensin receptor blockers (ACEi/ARB) and beta adrenergic antagonists (BB) were prescribed to nearly 67% and diuretic to 27% of TTC patients at discharge. All the studies followed up TTC patients post-discharge for a minimum of 3 months (inclusion criteria) and mean follow-up among the whole cohort was 24.5 months (95% CI, 19 months to 33 months). 74 cases of recurrence of TTC were detected during follow-up in the dataset of 1639 patients. The adjusted annual incidence of recurrence per 100
cases of TTC was calculated for all the individual studies (Fig. 2). There was significant heterogeneity (I2 = 77%) among the studies and annual incidence of recurrence was roughly 1.5%. Extensive data of cases of recurrence were reported in only nine studies. These nine studies comprised a pool of 504 patients and 23 associated events of recurrence of TTC at time intervals varying from 3 weeks to 72 months post index admission. The mean age of patients with recurrence was 65.5 years (95% CI, 62.1 to 68.9 years). Nearly all cases of recurrences occurred in women. This information was used to evaluate the incidence of recurrence over 6 month intervals from the time of diagnosis to a maximum follow-up of 6 years (Fig. 3). Cumulative incidence of recurrence increased from 1.2% at first 6 months to nearly 5% at 6 years. The incidence of recurrent chest pain in the absence of imaging and biochemical evidence of TTC was much higher and occurred in 14% of the patients requiring contact with cardiologist and/or hospital admission. We then evaluated the potential impact of BB and ACEi/ARB the incidence of recurrence. The proportion of patients discharged on BB and ACE/ARB on diagnosis of TTC and incidence of recurrence in 19 studies is described in Table 2. There was no significant association between the rate of recurrence and use of BB medication (P = 0.28) (Fig. 4A). However, there was a negative correlation between use of ACE/ARB use and rate of recurrence (P = 0.016, r = −0.45) (Fig. 4B). This correlation between reduced rates of recurrence and ACE/ARB treatment at discharge was also confirmed by chi squared test; there was a negative correlation of ACE/ARB with recurrence rate (P = 0.02) and no correlation of recurrence rate with BB use after discharge. The average LVEF during the first episode of TTC was much lower in the patients who had recurrence 33% (95% CI, 29% to 37%) than the whole pool 40% (95% CI, 39% to 41%). Despite a higher recurrence rate of TTC in cases where initial TTC was precipitated by emotional stress than physical illness, there was no statistically significant difference between the two groups. It was also noted that during recurrence the stressor could be different from the initial episode. Nearly 8% (128/1593) of patients who survived index admission died during the follow-up. Of the 128 deaths during follow-up, 27 were because of cardiac causes, 2 were related to TTC (one patients died during recurrence of TTC), 82 were because of non-cardiac issues and cause for 17 deaths was not specified. Only 4 studies reported on symptoms of dyspnea during the follow-up in these 11% of patients who complained of dyspnea during follow-up despite apparent resolution of the TTC changes and return of LVEF to the normal range. LVEF did
Table 2 Proportion of patients discharged on β-adrenergic blockers and angiotensin converting enzyme inhibitor and angiotensin receptor blockers (ACEi/ARB) in the different studies and the incidence of recurrence. Study
TTC no.
Discharge medications β-blocker
12
Traulle S Previtali M13 Eshtehardi P14 Spedicato L15 Mhmoud RE16 Regnate RE17 Teh AW19 Primetshofer D21 Parodi G25 Samardhi H26 Maekawa Y27 Núñez-Gil IJ30 Cacciotti L31 Vriz O32 Sharma V34 Showkathali R35 Pullara36 Tsuchihashi K39 Hertting K40
14 18 41 29 32 70 23 31 116 52 46 100 75 25 12 17 26 88 32
Recurrence TTC ACEi/ARB
No.
% of total
No.
% of total
No.
% of total
14 13 33 29 32 54 17 17 81 44 21 52 67 20 10 13 NA 16 20
100% 72% 80% 100% 100% 77% 74% 55% 70% 85% 46% 52% 89% 80% 83% 76% NA 18% 63%
13 12 34 2 NA 47 22 22 83 45 16 62 71 NA 12 15 25 13 26
93% 67% 83% 7% NA 67% 96% 71% 72% 87% 35% 62% 95% NA 100% 88% 96% 15% 81%
0 1 2 2 0 2 0 1 2 0 4 4 1 5 0 0 2 2 0
0% 6% 5% 7% 0% 3% 0% 3% 2% 0% 9% 4% 1% 20% 0% 0% 8% 2% 0%
TTC = takotsubo cardiomyopathy.
Please cite this article as: Singh K, et al, Systematic review and meta-analysis of incidence and correlates of recurrence of takotsubo cardiomyopathy, Int J Cardiol (2014), http://dx.doi.org/10.1016/j.ijcard.2014.04.221
K. Singh et al. / International Journal of Cardiology xxx (2014) xxx–xxx
A
B
Correlation Coefficient P Value
-.207 0.28
Correlation Coefficient P Value
-448 0.016
Fig. 4. The graph showing correlation of percentage of patients discharged on β-adrenergic blockers (Fig. 4A) and angiotensin converting enzyme inhibitor and angiotensin receptor blockers (ACE/ARB) (Fig. 4B) with incidence of recurrence. Each dot represents a separate study.
not normalize in a small proportion of patients (2.5%) who continued to have symptoms of heart failure. The information on symptoms of fatigue was only reported by one study. Overall, study quality was good with 16 out of the 26 criteria having at least 75% of all studies reporting a low risk of bias for bias. The main criteria which were not well reported across 75% of studies or more include justification of the number of included participants, reasons for non-inclusion of subjects, reporting of confounders, accounting for cofounders in the analyses, accounting for missing data in the analyses, impact of bias assessed qualitatively and impact of bias assessed quantitatively. 4. Discussion There is general agreement that TTC is usually precipitated by exposure to a “pulse” of released or administered catecholamines [6,7] and that individual susceptibility varies, being greater in aging females [8]. Furthermore, recurrence of TTC has been noted to be a problem from the earliest series [9] and definite management strategies regarding preventive treatment are awaiting appropriately designed trials. The complex nature of this disorder and lack of clear knowledge of
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pathogenesis are a hindrance in development of preventative treatment. While multiple hypotheses have been proposed to explain the pathogenesis of TTC the underlying etiology remains unclear. Case reports of development of TTC in family relatives and siblings have raised the possibility of genetic predisposition to TTC. In the mouse model of TTC, up regulation of transcriptional factors/immediate early genes (IEG) was found with emotional stress [10]. The research on the genetic basis of TTC has mainly been concentrated on the polymorphisms found in the adrenoceptors and has shown mixed results. Genetic polymorphism of the adrenoceptors has been linked with increased cardiac injury following subarachnoid hemorrhage, which is a well known cause of TTC like changes of left ventricle [11]. Spinelli et al. found that TTC patients exhibited a higher prevalence of leucine over glutamine variant of amino acid 41 of the G protein coupled receptor kinase 5(GRK5) non-catalytic regulatory domains [12]. On the other hand, no significant difference in the polymorphism of alpha and betaadrenergic receptors was found in the TTC and controls by other investigators [13,14]. The current study did not address the hypothesis that there might be a genetic basis to underlying recurrence risk in TTC (or indeed as regards index episodes). This task was impossible because none of the reported series included genotyping. We found that discharge strategies that included BB therapy appeared not to influence recurrence rates, while those utilizing ACEi or ARB were associated with significant decreases in recurrence rates as shown in Fig. 4. It is possible that pathogenesis of TTC may involve β2- rather than β1-adrenoceptor stimulation [15] and therefore the finding that (β1-selective) antagonists are ineffective is not totally surprising. We propose two possible explanations for reduction of recurrence with the use of ACEi or ARB. It could be either because of reduction in sympathetic activity through interaction with the renin–angiotensin system or because of the anti-inflammatory effects of ACEi or ARB on myocardium. Also, human and rat models of catecholamineinduced cardiac injury and TTC are associated with enhanced nitric oxide signaling [16–18], increased oxidative stress and development of intra-myocardial inflammatory change [19,20] Both ACEi and ARB exert anti-inflammatory effects and limit superoxide release with associated oxidative stress; hence they may well limit the biochemical process underlying onset of TTC [21,22]. In the series evaluated in the current review, the median annualized recurrent rate was around 1.5%. However, there was substantial heterogeneity between series, and it is certain that not all investigators utilized the full currently available spectrum of investigations to screen for recurrences. Furthermore, it is not clear how closely patients were followed up to detect subtle cases of TTC recurrence. Hence it is possible that the figure of 1.5% per annum represents an underestimate. It appeared that recurrence occurred significantly more commonly after attacks of TTC with associated severe LV dysfunction. There are two possible interpretations here: either severe attacks are indicative of increased patient susceptibility, or this represents the results of sensitization of patients to what was perceived as a severe index illness episode. The issue should be resolved by future series with more extensive detection methods to include all recurrences. Thus the current data, despite their potential inaccuracies, shed important light on the aspect of TTC. Even if the actual recurrence rate is of the order of 3–4% per annum, it would require a multicenter randomized study to evaluate pharmacotherapy to limit the problem. In the meantime, these data provide the first clue towards treatment potential. The main limitations of the current study arise from lack of clinical details on the episodes of recurrence in the publications. The missing information in the papers and ruling out non-English literature from the analysis were the other main limitations. Acknowledgment This work was supported in part by research grants from the National Health and Medical Research Council of Australia Grant Number APP
Please cite this article as: Singh K, et al, Systematic review and meta-analysis of incidence and correlates of recurrence of takotsubo cardiomyopathy, Int J Cardiol (2014), http://dx.doi.org/10.1016/j.ijcard.2014.04.221
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[31] Teh AW, New G, Cooke J. A single-centre report on the characteristics of tako-tsubo syndrome. Heart Lung Circ 2010;19:63–70. [32] Sharkey SW, Windenburg DC, Lesser JR, et al. Natural history and expansive clinical profile of stress (tako-tsubo) cardiomyopathy. J Am Coll Cardiol 2010;55:333–41. [33] Primetshofer D, Agladze R, Kratzer H, Reisinger J, Siostrzonek P. Tako-tsubo syndrome: an important differential diagnosis in patients with acute chest pain. Wien Klin Wochenschr 2010;122:37–44. [34] Song BG, Hahn JY, Cho SJ, et al. Clinical characteristics, ballooning pattern, and long-term prognosis of transient left ventricular ballooning syndrome. Heart Lung 2010;39:188–95. [35] Opolski G, Pawlak MM, Roik MF, et al. Clinical presentation, treatment, and long-term outcomes in patients with takotsubo cardiomyopathy. Experience of a single cardiology center. Pol Arch Med Wewn 2010;120:231–6. [36] Lee PH, Song JK, Sun BJ, et al. Outcomes of patients with stress-induced cardiomyopathy diagnosed by echocardiography in a tertiary referral hospital. J Am Soc Echocardiogr 2010;23:766–71. [37] Parodi G, Bellandi B, Del Pace S, et al. Natural history of tako-tsubo cardiomyopathy. Chest 2011;139:887–92. [38] Samardhi H, Raffel OC, Savage M, et al. Takotsubo cardiomyopathy: an Australian single centre experience with medium term follow up. Intern Med J 2012;42:35–42. [39] Maekawa Y, Kawamura A, Yuasa S, Nesto RW, Fukuda K. Direct comparison of takotsubo cardiomyopathy between Japan and USA: 3-year follow-up study. Intern Med 2012;51:257–62. [40] Pawlak M, Roik M, Kochanowski J, et al. Comparison of on-admission ST-segment elevation tako-tsubo patients and myocardial infarction women: in-hospital course and long-term follow-up. Kardiol Pol 2012;70:233–40. [41] Brenner R, Weilenmann D, Maeder MT, et al. Clinical characteristics, sex hormones, and long-term follow-up in Swiss postmenopausal women presenting with takotsubo cardiomyopathy. Clin Cardiol 2012;35:340–7. [42] Nunez-Gil IJ, Molina M, Bernardo E, et al. Tako-tsubo syndrome and heart failure: long-term follow-up. Rev Esp Cardiol 2012;65:996–1002. [43] Cacciotti L, Passaseo I, Marazzi G, et al. Observational study on takotsubo-like cardiomyopathy: clinical features, diagnosis, prognosis and follow-up. BMJ Open 2012;2. [44] Vriz O, Driussi C, Fazio MG, et al. Tako-tsubo cardiomyopathy: insights from a community hospital. J Cardiovasc Med 2013;14:576–81. [45] Patel SM, Chokka RG, Prasad K, Prasad A. Distinctive clinical characteristics according to age and gender in apical ballooning syndrome (takotsubo/stress cardiomyopathy): an analysis focusing on men and young women. J Card Fail 2013;19:306–10. [46] Sharma V, Srinivasan M, Sheehan DM, Ionescu A. Stress cardiomyopathy: case series and the review of literature. 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Please cite this article as: Singh K, et al, Systematic review and meta-analysis of incidence and correlates of recurrence of takotsubo cardiomyopathy, Int J Cardiol (2014), http://dx.doi.org/10.1016/j.ijcard.2014.04.221
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International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Systematic review and meta-analysis of incidence and correlates of recurrence of takotsubo cardiomyopathy☆ Kuljit Singh a,⁎, Kristin Carson b, Zafar Usmani b, Gagandeep Sawhney c, Ranjit Shah a, John Horowitz a a b c
Dept. of Cardiology, Queen Elizabeth Hospital, University of Adelaide, Adelaide, SA 5000, Australia Dept. of Respiratory Medicine, Basil Hetzel Institute, University of Adelaide, Adelaide, SA 5000, Australia The Madison Practice, Suite 6, 25 Hunter St., Hornsby, NSW 2077, Australia
a r t i c l e
i n f o
Article history: Received 17 March 2014 Received in revised form 17 April 2014 Accepted 19 April 2014 Available online xxxx Keywords: Recurrence Takotsubo cardiomyopathy Stress cardiomyopathy
a b s t r a c t Aim: Takotsubo cardiomyopathy (TTC) is a disorder of myocardial inflammation induced by high catecholamine levels and is associated with acute complications. In the long-term TTC is associated with a risk of single or multiple recurrences, but risk of such occurrences is not clear. We performed a systematic review and meta-analysis to identify and consolidate the evidence on the incidence and clinical correlates of cases of TTC recurrence. Methods: A comprehensive search of four major databases (EMBASE, OVID Medline, PubMed and Google Scholar) was performed from their inception to first week of Jan 2014. We included original research studies, recruiting ≥5 participants, with ≥3 months follow-up, published in English language that reported data on recurrence in patients with TTC. Results: Out of 298 studies searched, 31 cohorts (1664 TTC patients) were included in the analyses. Out of 74 cases of recurrence, with a mean follow-up of 24.5 months (95% CI, 19.3 to 33 months), extensive recurrence data were available for 23 cases. Cumulative incidence of recurrence was approximately 5% at 6 years. Annual rate of recurrence was approximately 1.5%. Furthermore, 14% of cases had recurrent chest pain and 11% reported dyspnea without definite evidence of recurrent TTC. Discharge medications at index admission included β-adrenoceptor antagonists (BB) in 66.8% and ACE inhibitors (ACEi) and ARB in 67.4%. Recurrence rate was independent of clinic utilization of BB prescription, but inversely correlated (r = −0.45, p = 0.016) with ACEi/ARB prescription. Patients with severe TTC at index admission were noted to have more recurrences. Conclusions: (1) TTC is associated with only 1–2% annual recurrence rate but substantially greater frequency of ongoing symptoms. (2) ACEi/ARB rather than BB may reduce risk of recurrence. © 2014 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Takotsubo cardiomyopathy (TTC) is now a well-known cardiac condition that predominantly affects women and can be associated with acute and chronic complications. Interestingly, TTC was first reported only 25 years ago in Japan and one of the earliest descriptions in humans was even more recent [1]. The acute stage of the disease can be complicated by hypotension, shock, arrhythmias, heart failure and death [2]. While our understanding of acute complication is clear, the knowledge of the natural history and long term TTC complications is limited because of relatively small number and limited follow-up of the patients. Recurrence of TTC is common and is a well reported long
☆ Disclosures: None. ⁎ Corresponding author at: Dept. of Cardiology, Queen Elizabeth Hospital, University of Adelaide, SA 5000. Tel.: +61 433 698 945; fax: +61 8312 4919. E-mail address: [email protected] (K. Singh).
term issue in TTC cohort [3]. However, the exact incidence and correlates of recurrence are not known. We therefore performed a meta-analysis and systematic review to determine the global incidence of recurrence of TTC and to consolidate the evidence. In the current study, we sought to determine utilizing a systematic review/meta-analysis approach the incidence of recurrence of TTC episodes and cause of its variability. We also prospectively evaluated the impact of discharge medications, left ventricular ejection fraction (LVEF) and type of stressor during initial episode on recurrence. 2. Methods This systematic review and meta-analysis is reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement guidelines. We included comparative studies of any design (randomized control trials, cohort, case control and cross sectional). Eligible studies needed to have ≥5 patients and a minimum follow-up of 3 months with confirmed documentation of recurrence of TTC. Inclusion of studies was limited to English language and foreign studies where translation in English was available. When data was reported from interrelating study samples (e.g., publications from the same group), the study with the highest number of
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Please cite this article as: Singh K, et al, Systematic review and meta-analysis of incidence and correlates of recurrence of takotsubo cardiomyopathy, Int J Cardiol (2014), http://dx.doi.org/10.1016/j.ijcard.2014.04.221
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K. Singh et al. / International Journal of Cardiology xxx (2014) xxx–xxx
Search Database: PubMed, Ovid Medline, Embase, Google Scholar Search Date: January 31, 2014. Search Strategy: (Takotsubo Cardiomyopath* or Broken Heart Syndrome or Stress Cardiomyopathy or Apical Ballooning Syndrome or Takotsubo Cardiomyopath*) and (Recurrence [MH] OR Recurrenc*[TW] OR Relapse*[TW] OR Reappearance*[TW] OR Incidence*[TW] OR Prevalence*[TW] OR Recurrent*[TW])
298 Abstracts were screened by for inclusion/exclusion criteria
6 Duplicate studies 12 follow up less than 3 months 3 Systematic reviews 4 studies did not report events during follow up 3 articles in foreign language without any translation in English 2 articles with less than 5 patients during follow up
240 abstracts were excluded based on screening of abstracts and titles for general criteria for inclusion and exclusion.
58 articles were selected for full-text review
28 articles were selected from the search + 3 other articles were selected from citations of other articles on TTC
31 articles fulfilled inclusion criteria and were selected for systematic review 1. ≥ 5 patients 2. ≥ 3 months of follow up provided 3. Incidences of recurrence during follow up clearly mentioned.
Fig. 1. Schematic of database search and identification of studies.
patients and the longest follow-up was included in the analysis. Single case reports, case series with less than 5 patients or where the follow-up was not conducted were not included. Systematic reviews of TTC were not included in the analysis. A thorough computer based search was performed using OVID MEDLINE, EMBASE, Google Scholar and PubMed databases. Search terms included (Takotsubo Cardiomyopath* [TW] OR Broken Heart Syndrome [TW] OR Stress Cardiomyopathy [TW] OR Apical Ballooning Syndrome [TW] OR Tako-Tsubo Cardiomyopath* [TW])) and (Recurrence [MH] OR Recurrence*[TW] OR Relapse*[TW] OR Reappearance*[TW] OR Incidence*[TW] OR Prevalence*[TW] OR Recurrent*[TW]). No limit to the start date was applied and the search was conducted up to 31 January 2014. We hand searched the references cited in the previous reviews and important articles on recurrence on TTC. We contacted the corresponding authors of the studies where relevant information was missing [4]. Two reviewers (KS and RS) screened all titles and abstracts individually. This was followed by the full manuscript review of the selected articles by the reviewers. One reviewer (KS) extracted data independently from selected studies using a standardized, pilot tested extraction template. The following data was extracted: study characteristics (author, country where investigation was conducted, study design, number of participants and objective of the study), participant characteristics (age and gender), clinical characteristics (ACS type for TTC, predisposing physical and emotion stressors, left ventricular ejection fraction (LVEF), acute complications, acute mortality, length of stay, discharge medications), recurrences (number and time of recurrence after initial diagnosis) and complications during long term follow up (death, chest pain, dyspnea, fatigue and heart failure). Two reviewers (RS and KS) assessed quality of included studies using a sub-set of the Tooth et.al, manuscript titled ‘Quality of Reporting of Observational Longitudinal Research’ [5], including only the 23 quality domains relevant to a meta-analysis of observational studies. We evaluated potential biases using classifications of ‘low risk of bias’ when data for the criterion were described, ‘high risk of bias’ when data were not stated and ‘unclear risk of bias’ when the criterion was not relevant to the study design. Review Manager software version 5.2 was used to make the risk of bias graph. Any classification, which was not straightforward, was solved by discussion with a third reviewer KC.
Continuous variables were reported as means ± standard deviation (SD), while skewed data were described as medians ± interquartile range. Categorical variables were reported using odds ratios (OR) with 95% confidence intervals (CI). If formal metaanalysis was not possible due to a skewed distribution of the number of patients between each study, we overlooked the individual studies and used data as if obtained from a single study. Studies with missing data were excluded from meta-analyses and details extrapolated in the quality and risk of bias assessments. We then used logistic regression to assess the relationship. Significant interaction between variables was considered when P b 0.05. All calculations were performed using Review Manager (RevMan, Computer program, Version 5.2, Copenhagen, The Nordic Cochrane Centre, The Cochrane Collaboration, 2012), SPSS 18.0 software (SPSS, IL, USA) and Microsoft Excel 2010. We divided the studies above and below the median level of percentage of ACE/ARB, BB and recurrence rate and performed Chi square test. The annual incidence of recurrence per hundred patients for each individual study was calculated. Formula for a CI for a population proportion was used to obtain CI for annual recurrence for each individual study.
3. Results The literature search on TTC and recurrence yielded 298 citations. The abstracts of all the 298 citations were reviewed and 58 articles were chosen for full text review. Of the 58 articles chosen for the full text review, 34 were selected as per the inclusion and exclusion criteria. Six out of 34 studies were noted to be duplicated (from the same group with overlapping patient data sets) and were excluded. Additional 3 articles were found on the hand search leading to a total of 31 [23,24, 25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47, 48,49,50,51,52,53] articles in the systematic review (Fig. 1). Authors
Please cite this article as: Singh K, et al, Systematic review and meta-analysis of incidence and correlates of recurrence of takotsubo cardiomyopathy, Int J Cardiol (2014), http://dx.doi.org/10.1016/j.ijcard.2014.04.221
K. Singh et al. / International Journal of Cardiology xxx (2014) xxx–xxx
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Table 1 Summary of basic characteristics of 32 studies included in this systematic review. No.
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31
Author
Year published
11
Kurowski V Traulle S12 Previtali M13 Eshtehardi P14 Spedicato L15 Mhmoud RE16 Regnate RE17 Dib C18 Teh AW19 Sharkey SW20 Primetshofer D21 Song BG22 Opolski G23 Lee PH24 Parodi G25 Samardhi H26 Maekawa Y27 Pawlak M28 Brenner R29 Núñez-Gil IJ30 Cacciotti L31 Vriz O32 Patel SM33 Sharma V34 Showkathali R35 Pullara36 Ribeiro VF37 Abdulla I38 Tsuchihashi K39 Hertting K40 Desmet WJR41
2007 2008 2009 2009 2008 2009 2009 2009 2010 2010 2010 2010 2010 2010 2011 2011 2011 2012 2012 2012 2012 2013 2013 2012 2013 2013 2013 2006 2001 2006 2003
Country
Germany France Italy Switzerland Italy France USA USA Australia USA Austria South Korea Poland South Korea Italy Australia USA/Japan Poland Switzerland Spain Italy Italy USA UK UK Italy Portugal Australia Japan Germany Belgium
TTC cases
35 14 18 41 29 32 70 105 23 136 31 87 31 56 116 52 46 41 17 100 75 25 224 12 17 26 37 35 88 32 13
Mean age (yrs)
72 70.4 72 65 64 71 67 66 65 68 75 NA 67 64 73 64 NA 69 66 68 72 66.8 NA 68 70 71 63 68 67 67.5 62.5
Gender
Mode of presentation
Variant
Presenting symptom
Women
Men
STEMI
NSTEMI
Apical
Non-apical
Chest pain
Dyspnoea
Other
33 13 18 35 25 31 67 100 20 130 28 64 29 44 106 51 43 39 17 89 72 21 212 10 17 22 35 35 76 29 12
2 1 0 6 4 1 3 5 3 6 3 23 2 20 10 1 3 2 0 11 3 4 12 2 0 4 2 1 12 3 1
24 7 10 16 18 17 29 35 16 67 13 28 24 16 70 10 29 29 5 60 34 20 101 4 17 NA 15 NA 79 12 4
11 7 8 25 11 15 41 70 7 69 8 59 7 40 46 42 14 12 12 40 41 5 123 8 0 NA 22 NA 9 20 9
21 NA NA 33 NA 28 NA NA NA 72 NA 55 NA 48 106 41 NA NA 16 NA 69 NA NA 12 NA 26 34 21 NA NA NA
14 NA NA 8 NA 4 NA NA NA 64 NA 32 NA 8 10 11 NA NA 1 NA 6 NA NA 0 NA 0 3 14 NA NA NA
NA 11 17 31 25 30 54 81 23 85 24 43 29 10 85 48 31 38 12 88 48 18 NA NA NA 26 33 NA 59 18 8
NA 4 2 10 3 1 28 8 NA 25 10 34 12 26 Na 6 24 14 5 NA 11 5 NA NA NA NA 3 NA 6 7 5
NA 0 1 NA 2 2 6 16 NA 26 1 0 20 NA 3 NA NA NA NA NA 4 NA NA NA NA 1 NA 23 7 NA
TTC = takotsubo cardiomyopathy. STEMI = ST elevation myocardial infarction. NSTEMI = non ST elevation myocardial infarction. UK = United Kingdom. USA = United States of America. NA = not available.
were contacted to obtain details of the patients with recurrence where it was not reported in the study. All the study designs were observational, including 20 retrospective, 10 prospective and one partially retrospective and partially prospective. Sample size ranged from 12 to 224 participants (total 1664). Twenty of these studies were from Europe, 3 were from Asia, 4 from the United States of America (USA), 3 from Australia and 1 study included participants from both USA and Japan. Basic characteristics of the studies are detailed in Table 1. Among the whole cohort of 1664 patients with TTC, 91.5% (n = 1523) were
women. The mean age of patients was 66 years (95% CI 63 to 69 years). In nearly 74% of patients TTC was preceded by physical/emotional stress and in the remaining 26% no obvious stressor was identified. Approximately 52% of patients presented as ST elevation myocardial infarction (STEMI) and the rest as non ST elevation myocardial infarction (NSTEMI). Presenting symptoms included chest pain in nearly 73% of cases and dyspnea in 18%, while in nearly 8% of patients TTC was diagnosed incidentally without either chest pain or dyspnea. Moderate LV systolic dysfunction was present in most of the patients with mean LVEF of 40% (95% CI 39% to 41%).
Fig. 2. Adjusted rate of recurrence per 100 patients per year among the studies included in the systematic review (shown in percentage).
Please cite this article as: Singh K, et al, Systematic review and meta-analysis of incidence and correlates of recurrence of takotsubo cardiomyopathy, Int J Cardiol (2014), http://dx.doi.org/10.1016/j.ijcard.2014.04.221
4
K. Singh et al. / International Journal of Cardiology xxx (2014) xxx–xxx
Fig. 3. Accumulative incidence of recurrence of takotsubo cardiomyopathy at 6-month intervals.
Acute complications were common. Death during index admission occurred in 3.5% of TTC cases. Acute heart failure was noted in 28% of cases, acute pulmonary odema in 21% and shock in 8% of the patients. Intubation, insertion of intra-aortic balloon pump and inotropic support during the shock/heart failure was common and the frequency of use varied from 7% to 18% in the studies mentioning this complication. Average length of hospital stay was 6.4 days (95% CI, 4.8 to 8 days). Nearly 80% of patients were discharged on anti-platelet medications (aspirin or clopidogrel). Angiotensin converting enzyme inhibitor/angiotensin receptor blockers (ACEi/ARB) and beta adrenergic antagonists (BB) were prescribed to nearly 67% and diuretic to 27% of TTC patients at discharge. All the studies followed up TTC patients post-discharge for a minimum of 3 months (inclusion criteria) and mean follow-up among the whole cohort was 24.5 months (95% CI, 19 months to 33 months). 74 cases of recurrence of TTC were detected during follow-up in the dataset of 1639 patients. The adjusted annual incidence of recurrence per 100
cases of TTC was calculated for all the individual studies (Fig. 2). There was significant heterogeneity (I2 = 77%) among the studies and annual incidence of recurrence was roughly 1.5%. Extensive data of cases of recurrence were reported in only nine studies. These nine studies comprised a pool of 504 patients and 23 associated events of recurrence of TTC at time intervals varying from 3 weeks to 72 months post index admission. The mean age of patients with recurrence was 65.5 years (95% CI, 62.1 to 68.9 years). Nearly all cases of recurrences occurred in women. This information was used to evaluate the incidence of recurrence over 6 month intervals from the time of diagnosis to a maximum follow-up of 6 years (Fig. 3). Cumulative incidence of recurrence increased from 1.2% at first 6 months to nearly 5% at 6 years. The incidence of recurrent chest pain in the absence of imaging and biochemical evidence of TTC was much higher and occurred in 14% of the patients requiring contact with cardiologist and/or hospital admission. We then evaluated the potential impact of BB and ACEi/ARB the incidence of recurrence. The proportion of patients discharged on BB and ACE/ARB on diagnosis of TTC and incidence of recurrence in 19 studies is described in Table 2. There was no significant association between the rate of recurrence and use of BB medication (P = 0.28) (Fig. 4A). However, there was a negative correlation between use of ACE/ARB use and rate of recurrence (P = 0.016, r = −0.45) (Fig. 4B). This correlation between reduced rates of recurrence and ACE/ARB treatment at discharge was also confirmed by chi squared test; there was a negative correlation of ACE/ARB with recurrence rate (P = 0.02) and no correlation of recurrence rate with BB use after discharge. The average LVEF during the first episode of TTC was much lower in the patients who had recurrence 33% (95% CI, 29% to 37%) than the whole pool 40% (95% CI, 39% to 41%). Despite a higher recurrence rate of TTC in cases where initial TTC was precipitated by emotional stress than physical illness, there was no statistically significant difference between the two groups. It was also noted that during recurrence the stressor could be different from the initial episode. Nearly 8% (128/1593) of patients who survived index admission died during the follow-up. Of the 128 deaths during follow-up, 27 were because of cardiac causes, 2 were related to TTC (one patients died during recurrence of TTC), 82 were because of non-cardiac issues and cause for 17 deaths was not specified. Only 4 studies reported on symptoms of dyspnea during the follow-up in these 11% of patients who complained of dyspnea during follow-up despite apparent resolution of the TTC changes and return of LVEF to the normal range. LVEF did
Table 2 Proportion of patients discharged on β-adrenergic blockers and angiotensin converting enzyme inhibitor and angiotensin receptor blockers (ACEi/ARB) in the different studies and the incidence of recurrence. Study
TTC no.
Discharge medications β-blocker
12
Traulle S Previtali M13 Eshtehardi P14 Spedicato L15 Mhmoud RE16 Regnate RE17 Teh AW19 Primetshofer D21 Parodi G25 Samardhi H26 Maekawa Y27 Núñez-Gil IJ30 Cacciotti L31 Vriz O32 Sharma V34 Showkathali R35 Pullara36 Tsuchihashi K39 Hertting K40
14 18 41 29 32 70 23 31 116 52 46 100 75 25 12 17 26 88 32
Recurrence TTC ACEi/ARB
No.
% of total
No.
% of total
No.
% of total
14 13 33 29 32 54 17 17 81 44 21 52 67 20 10 13 NA 16 20
100% 72% 80% 100% 100% 77% 74% 55% 70% 85% 46% 52% 89% 80% 83% 76% NA 18% 63%
13 12 34 2 NA 47 22 22 83 45 16 62 71 NA 12 15 25 13 26
93% 67% 83% 7% NA 67% 96% 71% 72% 87% 35% 62% 95% NA 100% 88% 96% 15% 81%
0 1 2 2 0 2 0 1 2 0 4 4 1 5 0 0 2 2 0
0% 6% 5% 7% 0% 3% 0% 3% 2% 0% 9% 4% 1% 20% 0% 0% 8% 2% 0%
TTC = takotsubo cardiomyopathy.
Please cite this article as: Singh K, et al, Systematic review and meta-analysis of incidence and correlates of recurrence of takotsubo cardiomyopathy, Int J Cardiol (2014), http://dx.doi.org/10.1016/j.ijcard.2014.04.221
K. Singh et al. / International Journal of Cardiology xxx (2014) xxx–xxx
A
B
Correlation Coefficient P Value
-.207 0.28
Correlation Coefficient P Value
-448 0.016
Fig. 4. The graph showing correlation of percentage of patients discharged on β-adrenergic blockers (Fig. 4A) and angiotensin converting enzyme inhibitor and angiotensin receptor blockers (ACE/ARB) (Fig. 4B) with incidence of recurrence. Each dot represents a separate study.
not normalize in a small proportion of patients (2.5%) who continued to have symptoms of heart failure. The information on symptoms of fatigue was only reported by one study. Overall, study quality was good with 16 out of the 26 criteria having at least 75% of all studies reporting a low risk of bias for bias. The main criteria which were not well reported across 75% of studies or more include justification of the number of included participants, reasons for non-inclusion of subjects, reporting of confounders, accounting for cofounders in the analyses, accounting for missing data in the analyses, impact of bias assessed qualitatively and impact of bias assessed quantitatively. 4. Discussion There is general agreement that TTC is usually precipitated by exposure to a “pulse” of released or administered catecholamines [6,7] and that individual susceptibility varies, being greater in aging females [8]. Furthermore, recurrence of TTC has been noted to be a problem from the earliest series [9] and definite management strategies regarding preventive treatment are awaiting appropriately designed trials. The complex nature of this disorder and lack of clear knowledge of
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pathogenesis are a hindrance in development of preventative treatment. While multiple hypotheses have been proposed to explain the pathogenesis of TTC the underlying etiology remains unclear. Case reports of development of TTC in family relatives and siblings have raised the possibility of genetic predisposition to TTC. In the mouse model of TTC, up regulation of transcriptional factors/immediate early genes (IEG) was found with emotional stress [10]. The research on the genetic basis of TTC has mainly been concentrated on the polymorphisms found in the adrenoceptors and has shown mixed results. Genetic polymorphism of the adrenoceptors has been linked with increased cardiac injury following subarachnoid hemorrhage, which is a well known cause of TTC like changes of left ventricle [11]. Spinelli et al. found that TTC patients exhibited a higher prevalence of leucine over glutamine variant of amino acid 41 of the G protein coupled receptor kinase 5(GRK5) non-catalytic regulatory domains [12]. On the other hand, no significant difference in the polymorphism of alpha and betaadrenergic receptors was found in the TTC and controls by other investigators [13,14]. The current study did not address the hypothesis that there might be a genetic basis to underlying recurrence risk in TTC (or indeed as regards index episodes). This task was impossible because none of the reported series included genotyping. We found that discharge strategies that included BB therapy appeared not to influence recurrence rates, while those utilizing ACEi or ARB were associated with significant decreases in recurrence rates as shown in Fig. 4. It is possible that pathogenesis of TTC may involve β2- rather than β1-adrenoceptor stimulation [15] and therefore the finding that (β1-selective) antagonists are ineffective is not totally surprising. We propose two possible explanations for reduction of recurrence with the use of ACEi or ARB. It could be either because of reduction in sympathetic activity through interaction with the renin–angiotensin system or because of the anti-inflammatory effects of ACEi or ARB on myocardium. Also, human and rat models of catecholamineinduced cardiac injury and TTC are associated with enhanced nitric oxide signaling [16–18], increased oxidative stress and development of intra-myocardial inflammatory change [19,20] Both ACEi and ARB exert anti-inflammatory effects and limit superoxide release with associated oxidative stress; hence they may well limit the biochemical process underlying onset of TTC [21,22]. In the series evaluated in the current review, the median annualized recurrent rate was around 1.5%. However, there was substantial heterogeneity between series, and it is certain that not all investigators utilized the full currently available spectrum of investigations to screen for recurrences. Furthermore, it is not clear how closely patients were followed up to detect subtle cases of TTC recurrence. Hence it is possible that the figure of 1.5% per annum represents an underestimate. It appeared that recurrence occurred significantly more commonly after attacks of TTC with associated severe LV dysfunction. There are two possible interpretations here: either severe attacks are indicative of increased patient susceptibility, or this represents the results of sensitization of patients to what was perceived as a severe index illness episode. The issue should be resolved by future series with more extensive detection methods to include all recurrences. Thus the current data, despite their potential inaccuracies, shed important light on the aspect of TTC. Even if the actual recurrence rate is of the order of 3–4% per annum, it would require a multicenter randomized study to evaluate pharmacotherapy to limit the problem. In the meantime, these data provide the first clue towards treatment potential. The main limitations of the current study arise from lack of clinical details on the episodes of recurrence in the publications. The missing information in the papers and ruling out non-English literature from the analysis were the other main limitations. Acknowledgment This work was supported in part by research grants from the National Health and Medical Research Council of Australia Grant Number APP
Please cite this article as: Singh K, et al, Systematic review and meta-analysis of incidence and correlates of recurrence of takotsubo cardiomyopathy, Int J Cardiol (2014), http://dx.doi.org/10.1016/j.ijcard.2014.04.221
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Please cite this article as: Singh K, et al, Systematic review and meta-analysis of incidence and correlates of recurrence of takotsubo cardiomyopathy, Int J Cardiol (2014), http://dx.doi.org/10.1016/j.ijcard.2014.04.221
